tbuckley/cabot-search huggingface dataset:
Therapist-guided internet-based psychodynamic therapy versus cognitive behavioural therapy for adolescent depression in Sweden: a randomised, clinical, non-inferiority trial
Authors: Jakob Mechler, Karin Lindqvist, Per Carlbring, Naira Topooco, Fredrik Falkenström, Peter Lilliengren, Gerhard Andersson, Robert Johansson, Nick Midgley, Julian Edbrooke-Childs, Hanne-Sofie J Dahl, Rolf Sandell, Agneta Thorén, Randi Ulberg, Katja Lindert Bergsten, Björn Philips
Journal: The Lancet Digital Health (2022)

Adolescent major depressive disorder (MDD) is highly prevalent and associated with lifelong adversity. Evidence-based treatments exist, but accessible treatment alternatives are needed. We aimed to compare internet-based psychodynamic therapy (IPDT) with an established evidence-based treatment (internet-based cognitive behavioural therapy [ICBT]) for the treatment of adolescents with depression.In this randomised, clinical trial, we tested whether IPDT was non-inferior to ICBT in the treatment of adolescent MDD. Eligible participants were 15-19 years old, presenting with a primary diagnosis of MDD according to DSM-5. Participants were recruited nationwide in Sweden through advertisements on social media, as well as contacts with junior and senior high schools, youth associations, social workers, and health-care providers. Adolescents who scored 9 or higher on the Quick Inventory of Depressive Symptomatology for Adolescents (QIDS-A17-SR) in an initial online screening were contacted by telephone for a diagnostic assessment using the Mini International Neuropsychiatric Interview. Participants were randomly assigned to ICBT or IPDT. Both interventions comprised eight self-help modules delivered over 10 weeks on a secure online platform. The primary outcome was change in depression severity measured weekly by the QIDS-A17-SR. Primary analyses were based on an intention-to-treat sample including all participants randomly assigned. A non-inferiority margin of Cohen's d=0·30 was predefined. The study is registered at ISRCTN, ISRCTN12552584.Between Aug 19, 2019, and Oct 7, 2020, 996 young people completed screening; 516 (52%) were contacted for a diagnostic interview. 272 participants were eligible and randomly assigned to ICBT (n=136) or IPDT (n=136). In the ICBT group, 51 (38%) of 136 participants were classified as remitted, and 54 (40%) of 136 participants were classified as remitted in the IPDT group. Within-group effects were large (ICBT: within-group d=1·75, 95% CI 1·49 to 2·01; IPDT: within-group d=1·93, 1·67 to 2·20; both p<0·0001). No statistically significant treatment difference was found in the intention-to-treat analysis. Non-inferiority for IPDT was shown for the estimated change in depression during treatment (d=-0·18, 90% CI -0·49 to 0·13; p=0·34). All secondary outcomes showed non-significant between-group differences.IPDT was non-inferior to ICBT in terms of change in depression for the treatment of adolescents with MDD. This finding increases the range of accessible and effective treatment alternatives for adolescents with depression.Kavli trust.
Plasma and memory antibody responses to Gamma SARS-CoV-2 provide limited cross-protection to other variants
Authors: Marianna Agudelo, Frauke Muecksch, Dennis Schaefer-Babajew, Alice Cho, Justin DaSilva, Eva Bednarski, Victor Ramos, Thiago Y. Oliveira, Melissa Cipolla, Anna Gazumyan, Shuai Zong, Danielle A.S. Rodrigues, Guilherme S. Lira, Luciana Conde, Renato Santana Aguiar, Orlando C. Ferreira, Amilcar Tanuri, Katia C. Affonso, Rafael M. Galliez, Terezinha Marta Pereira Pinto Castineiras, Juliana Echevarria-Lima, Marcelo Torres Bozza, Andre M. Vale, Paul D. Bieniasz, Theodora Hatziioannou, Michel C. Nussenzweig
Journal: The Journal of Experimental Medicine (2022)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be a global problem in part because of the emergence of variants of concern that evade neutralization by antibodies elicited by prior infection or vaccination. Here we report on human neutralizing antibody and memory responses to the Gamma variant in a cohort of hospitalized individuals. Plasma from infected individuals potently neutralized viruses pseudotyped with Gamma SARS-CoV-2 spike protein, but neutralizing activity against Wuhan-Hu-1-1, Beta, Delta, or Omicron was significantly lower. Monoclonal antibodies from memory B cells also neutralized Gamma and Beta pseudoviruses more effectively than Wuhan-Hu-1. 69% and 34% of Gamma-neutralizing antibodies failed to neutralize Delta or Wuhan-Hu-1. Although Class 1 and 2 antibodies dominate the response to Wuhan-Hu-1 or Beta, 54% of antibodies elicited by Gamma infection recognized Class 3 epitopes. The results have implications for variant-specific vaccines and infections, suggesting that exposure to variants generally provides more limited protection to other variants.
Effect of positive microbiological testing on antibiotic de-escalation and outcomes in community-acquired pneumonia: a propensity score analysis
Authors: Gabriela Abelenda-Alonso, Alexander Rombauts, Carlota Gudiol, Esther García-Lerma, Natalia Pallarés, Carmen Ardanuy, Laura Calatayud, Jordi Niubó, Cristian Tebé, Jordi Carratalà
Journal: Clinical Microbiology and Infection (2022)

The usefulness of routine microbiological testing for rationalising antibiotic use in hospitalised patients with community-acquired pneumonia (CAP) continues to be a subject of debate. We aim to determine the effect of positive microbiological testing on antimicrobial de-escalation and clinical outcomes in CAP.A retrospective analysis of a prospectively collected cohort of non-immunosuppressed adults hospitalised with CAP was performed. The primary study outcome was antimicrobial de-escalation. Secondary outcomes included 30-day case-fatality rate, adverse events, and CAP recurrence. Adjustment for confounders was performed by inverse probability weighting propensity score, logistic regression, and cause-specific Cox model.Of 3677 patients with CAP, 1924 (52.3%) had any positive microbiological test. Antimicrobial de-escalation was performed in 648/1924 (33.7%) of patients with positive microbiological testing and in 179/1753 (10.2%) of those with non-positive results. When propensity score was entered into the multivariate analysis, positive microbiological testing (adjusted OR (AOR)], 2.59; 1.96-3.41) and clinical stability at day 3 (AOR 1.87; 1.45-2.10) were two of the main factors independently associated with antimicrobial de-escalation. After applying an adjusted cause-specific Cox model, antimicrobial de-escalation was not associated with a higher 30-day case-fatality rate (adjusted hazard ratio (AHR), 0.44 (95% CI, 0.14-1.43)), higher frequency of adverse events (AHR, 0.77 (95% CI, 0.53-1.12)), or CAP recurrence (AHR, 0.65 (95% CI, 0.35-1.14)).Antimicrobial de-escalation was more often performed in hospitalised patients with CAP who had positive microbiological tests than in those with non-positive results, and it did not adversely affect relevant clinical outcomes.
Sajid Javid: A year in the job, what is his legacy?
Authors: Ingrid Torjesen
Journal: BMJ (2022)

<h3>Background</h3> Traditional strategies for surveillance of surgical site infections (SSI) have multiple limitations, including delayed and incomplete outbreak detection. Statistical process control (SPC) methods address these deficiencies by combining longitudinal analysis with graphical presentation of data. <h3>Methods</h3> We performed a pilot study within a large network of community hospitals to evaluate performance of SPC methods for detecting SSI outbreaks. We applied conventional Shewhart and exponentially weighted moving average (EWMA) SPC charts to 10 previously investigated SSI outbreaks that occurred from 2003 to 2013. We compared the results of SPC surveillance to the results of traditional SSI surveillance methods. Then, we analysed the performance of modified SPC charts constructed with different outbreak detection rules, EWMA smoothing factors and baseline SSI rate calculations. <h3>Results</h3> Conventional Shewhart and EWMA SPC charts both detected 8 of the 10 SSI outbreaks analysed, in each case prior to the date of traditional detection. Among detected outbreaks, conventional Shewhart chart detection occurred a median of 12 months prior to outbreak onset and 22 months prior to traditional detection. Conventional EWMA chart detection occurred a median of 7months prior to outbreak onset and 14 months prior to traditional detection. Modified Shewhart and EWMA charts additionally detected several outbreaks earlier than conventional SPC charts. Shewhart and SPC charts had low false-positive rates when used to analyse separate control hospital SSI data. <h3>Conclusions</h3> Our findings illustrate the potential usefulness and feasibility of real-time SPC surveillance of SSI to rapidly identify outbreaks and improve patient safety. Further study is needed to optimise SPC chart selection and calculation, statistical outbreak detection rules and the process for reacting to signals of potential outbreaks.
The minimum number of examined lymph nodes for accurate nodal staging and optimal survival of stage T1-2 esophageal squamous cell carcinoma: A retrospective multicenter cohort with SEER database validation
Authors: Dong Tian, Hao-Xuan Li, Yu-Shang Yang, Hao-Ji Yan, Kai-Yuan Jiang, Yin-Bin Zheng, Zheng-Dong Zong, Han-Lu Zhang, Xiao-Guang Guo, Hong-Ying Wen, Long-Qi Chen
Journal: International Journal of Surgery (2022)
RNA helicase DEAD‐box protein 5 alleviates nonalcoholic steatohepatitis progression via tethering TSC complex and suppressing mTORC1 signaling
Authors: Yanqiu Zhang, Shengtao Ye, Weijia Lu, Jiawen Zhong, Yingrong Leng, Ting Yang, Jun Luo, Wenjun Xu, Hao Zhang, Lingyi Kong
Journal: Hepatology (2022)

Background and Aims: Nonalcoholic fatty liver disease and its progressive form, nonalcoholic steatohepatitis (NASH), are rapidly becoming the top causes of hepatocellular carcinoma (HCC). Currently, there are no approved therapies for the treatment of NASH. DEAD‐box protein 5 (DDX5) plays important roles in different cellular processes. However, the precise role of DDX5 in NASH remains unclear. Approach and Results: DDX5 expression was downregulated in patients with NASH, mouse models with diet‐induced NASH (high‐fat diet [HFD], methionine‐ and choline‐deficient diet, and choline‐deficient HFD), mouse models with NASH‐HCC (diethylnitrosamine with HFD), and palmitic acid–stimulated hepatocytes. Adeno‐associated virus–mediated DDX5 overexpression ameliorates hepatic steatosis and inflammation, whereas its deletion worsens such pathology. The untargeted metabolomics analysis was carried out to investigate the mechanism of DDX5 in NASH and NASH‐HCC, which suggested the regulatory effect of DDX5 on lipid metabolism. DDX5 inhibits mechanistic target of rapamycin complex 1 (mTORC1) activation by recruiting the tuberous sclerosis complex (TSC)1/2 complex to mTORC1, thus improving lipid metabolism and attenuating the NACHT‐, leucine‐rich‐repeat (LRR)‐, and pyrin domain (PYD)‐containing protein 3 inflammasome activation. We further identified that the phytochemical compound hyperforcinol K directly interacted with DDX5 and prevented its ubiquitinated degradation mediated by ubiquitin ligase (E3) tripartite motif protein 5, thereby significantly reducing lipid accumulation and inflammation in a NASH mouse model. Conclusions: These findings provide mechanistic insight into the role of DDX5 in mTORC1 regulation and NASH progression, as well as suggest a number of targets and a promising lead compound for therapeutic interventions against NASH.
Inhibition of stearoyl-CoA desaturase 1 (SCD1) enhances the antitumor T cell response through regulating β-catenin signaling in cancer cells and ER stress in T cells and synergizes with anti-PD-1 antibody
Authors: Yuki Katoh, Tomonori Yaguchi, Akiko Kubo, Takashi Iwata, Kenji Morii, Daiki Kato, Shigeki Ohta, Ryosuke Satomi, Yasuhiro Yamamoto, Yoshitaka Oyamada, Kota Ouchi, Shin Takahashi, Chikashi Ishioka, Ryo Matoba, Makoto Suematsu, Yutaka Kawakami
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Understanding the mechanisms of non-T cell inflamed tumor microenvironment (TME) and their modulation are important to improve cancer immunotherapies such as immune checkpoint inhibitors. The involvement of various immunometabolisms has recently been indicated in the formation of immunosuppressive TME. In this study, we investigated the immunological roles of stearoyl-CoA desaturase 1 (SCD1), which is essential for fatty acid metabolism, in the cancer immune response. Methods We investigated the roles of SCD1 by inhibition with the chemical inhibitor or genetic manipulation in antitumor T cell responses and the therapeutic effect of anti-programmed cell death protein 1 (anti-PD-1) antibody using various mouse tumor models, and their cellular and molecular mechanisms. The roles of SCD1 in human cancers were also investigated by gene expression analyses of colon cancer tissues and by evaluating the related free fatty acids in sera obtained from patients with non-small cell lung cancer who were treated with anti-PD-1 antibody. Results Systemic administration of a SCD1 inhibitor in mouse tumor models enhanced production of CCL4 by cancer cells through reduction of Wnt/β-catenin signaling and by CD8 + effector T cells through reduction of endoplasmic reticulum stress. It in turn promoted recruitment of dendritic cells (DCs) into the tumors and enhanced the subsequent induction and tumor accumulation of antitumor CD8 + T cells. SCD1 inhibitor was also found to directly stimulate DCs and CD8 + T cells. Administration of SCD1 inhibitor or SCD1 knockout in mice synergized with an anti-PD-1 antibody for its antitumor effects in mouse tumor models. High SCD1 expression was observed in one of the non-T cell-inflamed subtypes in human colon cancer, and serum SCD1 related fatty acids were correlated with response rates and prognosis of patients with non-small lung cancer following anti-PD-1 antibody treatment. Conclusions SCD1 expressed in cancer cells and immune cells causes immunoresistant conditions, and its inhibition augments antitumor T cells and therapeutic effects of anti-PD-1 antibody. Therefore, SCD1 is an attractive target for the development of new diagnostic and therapeutic strategies to improve current cancer immunotherapies including immune checkpoint inhibitors.
Regulating Macrophage Polarization in High Glucose Microenvironment Using Lithium‐Modified Bioglass‐Hydrogel for Diabetic Bone Regeneration (Adv. Healthcare Mater. 13/2022)
Authors: Zerui Wu, Jiaxiang Bai, Gaoran Ge, Tao Wang, Shuo Feng, Qiaoqiao Ma, Xiaolong Liang, Wenming Li, Wei Zhang, Yaozeng Xu, Kaijin Guo, Wenguo Cui, Guochun Zha, Dechun Geng
Journal: Advanced Healthcare Materials (2022)

Bone Regeneration In article number 2200298 by Wenguo Cui, Guochun Zha, Dechun Geng, and co-workers, a kind of lithium-based bioglasshydrogel is implanted in a femoral defect in diabetic rats. Photo-crosslinked hydrogel triggered by blue light releases Si4+, Li+ and other ions to promote osteogenesis, angiogenesis and anti-inflammation. This work represents the delightful approach of orchestrating diabetic bone regeneration on the basis of high glucose microenvironment.
A high-resolution single-molecule sequencing-based Arabidopsis transcriptome using novel methods of Iso-seq analysis
Authors: Runxuan Zhang, Richard Kuo, Max Coulter, Cristiane P. G. Calixto, Juan Carlos Entizne, Wenbin Guo, Yamile Marquez, Linda Milne, Stefan Riegler, Akihiro Matsui, Maho Tanaka, Sarah Harvey, Yubang Gao, Theresa Wießner-Kroh, Alejandro Paniagua, Martin Crespi, Katherine Denby, Asa ben Hur, Enamul Huq, Michael Jantsch, Artur Jarmolowski, Tino Koester, Sascha Laubinger, Qingshun Quinn Li, Lianfeng Gu, Motoaki Seki, Dorothee Staiger, Ramanjulu Sunkar, Zofia Szweykowska-Kulinska, Shih-Long Tu, Andreas Wachter, Robbie Waugh, Liming Xiong, Xiao-Ning Zhang, Ana Conesa, Anireddy S. N. Reddy, Andrea Barta, Maria Kalyna, John W. S. Brown
Journal: Genome biology (2022)

Accurate and comprehensive annotation of transcript sequences is essential for transcript quantification and differential gene and transcript expression analysis. Single-molecule long-read sequencing technologies provide improved integrity of transcript structures including alternative splicing, and transcription start and polyadenylation sites. However, accuracy is significantly affected by sequencing errors, mRNA degradation, or incomplete cDNA synthesis.We present a new and comprehensive Arabidopsis thaliana Reference Transcript Dataset 3 (AtRTD3). AtRTD3 contains over 169,000 transcripts-twice that of the best current Arabidopsis transcriptome and including over 1500 novel genes. Seventy-eight percent of transcripts are from Iso-seq with accurately defined splice junctions and transcription start and end sites. We develop novel methods to determine splice junctions and transcription start and end sites accurately. Mismatch profiles around splice junctions provide a powerful feature to distinguish correct splice junctions and remove false splice junctions. Stratified approaches identify high-confidence transcription start and end sites and remove fragmentary transcripts due to degradation. AtRTD3 is a major improvement over existing transcriptomes as demonstrated by analysis of an Arabidopsis cold response RNA-seq time-series. AtRTD3 provides higher resolution of transcript expression profiling and identifies cold-induced differential transcription start and polyadenylation site usage.AtRTD3 is the most comprehensive Arabidopsis transcriptome currently. It improves the precision of differential gene and transcript expression, differential alternative splicing, and transcription start/end site usage analysis from RNA-seq data. The novel methods for identifying accurate splice junctions and transcription start/end sites are widely applicable and will improve single-molecule sequencing analysis from any species.
C reactive protein utilisation, a biomarker for early COVID-19 treatment, improves lenzilumab efficacy: results from the randomised phase 3 ‘LIVE-AIR’ trial
Authors: Zelalem Temesgen, Colleen F Kelley, Frank Cerasoli, Adrian Kilcoyne, Dale Chappell, Cameron Durrant, Omar Ahmed, Gabrielle Chappell, Victoria Catterson, Christopher Polk, Andrew Badley, Vincent C Marconi
Journal: Thorax (2022)

COVID-19 severity is correlated with granulocyte macrophage colony-stimulating factor (GM-CSF) and C reactive protein (CRP) levels. In the phase three LIVE-AIR trial, lenzilumab an anti-GM-CSF monoclonal antibody, improved the likelihood of survival without ventilation (SWOV) in COVID-19, with the greatest effect in participants having baseline CRP below a median of 79 mg/L. Herein, the utility of baseline CRP to guide lenzilumab treatment was assessed.A subanalysis of the randomised, blinded, controlled, LIVE-AIR trial in which lenzilumab or placebo was administered on day 0 and participants were followed through Day 28.Hospitalised COVID-19 participants (N=520) with SpO2 ≤94% on room air or requiring supplemental oxygen but not invasive mechanical ventilation.Lenzilumab (1800 mg; three divided doses, q8h, within 24 hours) or placebo infusion alongside corticosteroid and remdesivir treatments.The primary endpoint was the time-to-event analysis difference in SWOV through day 28 between lenzilumab and placebo treatments, stratified by baseline CRP.SWOV was achieved in 152 (90%; 95% CI 85 to 94) lenzilumab and 144 (79%; 72 to 84) placebo-treated participants with baseline CRP <150 mg/L (HR: 2.54; 95% CI 1.46 to 4.41; p=0.0009) but not with CRP ≥150 mg/L (HR: 1.04; 95% CI 0.51 to 2.14; p=0.9058). A statistically significant interaction between CRP and lenzilumab treatment was observed (p=0.044). Grade ≥3 adverse events with lenzilumab were comparable to placebo in both CRP strata. No treatment-emergent serious adverse events were attributed to lenzilumab.Hospitalised hypoxemic patients with COVID-19 with baseline CRP <150 mg/L derived the greatest clinical benefit from treatment with lenzilumab.NCT04351152; ClinicalTrials.gov.
Two phenotypes that predict prognosis in lung adenocarcinoma
Authors: Lukas Kalinke, Sam M. Janes
Journal: European Respiratory Journal (2022)

A lung cancer patient's prognosis is defined by a combination of the cancer stage, which defines the cancer location and spread; the patient's performance status, acting as an indirect measure of their ability to tolerate treatment; and finally, more intrinsic tumour-related properties such as the local immune contexture and tumour genetic makeup. The latter two dictate whether immunotherapy and targeted agents are treatment options. Histopathological biomarkers can predict survival in patients with resected lung adenocarcinoma <https://bit.ly/3JN2HzL>
<scp>BRD4</scp> degradation blocks expression of <scp>MYC</scp> and multiple forms of stem cell resistance in Ph<sup>+</sup> chronic myeloid leukemia
Authors: Barbara Peter, Gregor Eisenwort, Irina Sadovnik, Karin Bauer, Michael Willmann, Thomas Rülicke, Daniela Berger, Gabriele Stefanzl, Georg Greiner, Gregor Hoermann, Alexandra Keller, Dominik Wolf, Martin Čulen, Georg E. Winter, Thomas Hoffmann, Ana‐Iris Schiefer, Wolfgang R. Sperr, Johannes Zuber, Jiří Mayer, Peter Valent
Journal: American Journal of Hematology (2022)

Abstract In most patients with chronic myeloid leukemia (CML) clonal cells can be kept under control by BCR::ABL1 tyrosine kinase inhibitors (TKI). However, overt resistance or intolerance against these TKI may occur. We identified the epigenetic reader BRD4 and its downstream‐effector MYC as growth regulators and therapeutic targets in CML cells. BRD4 and MYC were found to be expressed in primary CML cells, CD34 + /CD38 − leukemic stem cells (LSC), and in the CML cell lines KU812, K562, KCL22, and KCL22 T315I . The BRD4‐targeting drug JQ1 was found to suppress proliferation in KU812 cells and primary leukemic cells in the majority of patients with chronic phase CML. In the blast phase of CML, JQ1 was less effective. However, the BRD4 degrader dBET6 was found to block proliferation and/or survival of primary CML cells in all patients tested, including blast phase CML and CML cells exhibiting the T315I variant of BCR::ABL1. Moreover, dBET6 was found to block MYC expression and to synergize with BCR::ABL1 TKI in inhibiting the proliferation in the JQ1‐resistant cell line K562. Furthermore, BRD4 degradation was found to overcome osteoblast‐induced TKI resistance of CML LSC in a co‐culture system and to block interferon‐gamma‐induced upregulation of the checkpoint antigen PD‐L1 in LSC. Finally, dBET6 was found to suppress the in vitro survival of CML LSC and their engraftment in NSG mice. Together, targeting of BRD4 and MYC through BET degradation sensitizes CML cells against BCR::ABL1 TKI and is a potent approach to overcome multiple forms of drug resistance in CML LSC.